Hindawi

International Journal of Rheumatology

Volume 2018, Article ID 2586916, 5 pages
https://doi.org/10.1155/2018/2586916

Research Article
The Effect of Prednisone on Tuberculin Skin Test Reaction in
Patients with Rheumatoid Arthritis

Olga Reitblat,1,2 Tsahi T. Lerman,1,2 Ornit Cohen,1,2 and Tatiana Reitblat 1,2,3

1
Barzilai Medical Center, Ashkelon, Israel
2
Ben Gurion University of the Negev, Beer-Sheva, Israel
3
Rheumatology Unit, Barzilai Medical Center, Ashkelon, Israel

Correspondence should be addressed to Tatiana Reitblat; reitblat@barzi.health.gov.il

Received 18 April 2018; Revised 29 July 2018; Accepted 3 October 2018; Published 21 October 2018

Academic Editor: Charles J. Malemud

Copyright © 2018 Olga Reitblat et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. To assess the correlation between prednisone and methotrexate (MTX) treatment duration and dosage with the
TST induration diameter of the TST reaction among rheumatoid arthritis (RA) patients. Method. We retrospectively analyzed
consecutive cases of RA patients who were TNF-i therapy candidates. TST measurements, prednisone and methotrexate dosages,
and treatment durations were recorded. A control group was randomly selected from healthy subjects. We compared TST reaction
size between the following three groups: RA patients with current prednisone treatment, RA prednisone naı̈ve patients, and healthy
individuals. Results. Our study sample comprised 43 RA patients with prednisone treatment, 22 prednisone naı̈ve patients, and 195
healthy subjects. There was no significant difference in mean TST between the groups (5.3±6.6, 7.8±6.2, and 7.6±7.0, respectively,
p=0.149). No correlation was noted between TST size and prednisone u-y (r=0.229, p=0.140) or methotrexate u-y in patients with
and without prednisone therapy (r=0.219, p=0.158; and r=−0.293, p=0.186, respectively). Conclusions. Our results show that the
TST reaction size among RA patients may not be affected by prednisone therapy. In addition, the TST reaction of RA patients may
present similarly to that of healthy individuals. Therefore, we suggest that the criterion of a TST reaction of 5 mm to define latent
TB infection in our population should be reevaluated.

1. Introduction incidence of TB infection in several studies, including a large

With almost 8 million new tuberculosis (TB) cases reported
annually, TB morbidity and mortality remain major prob-
lems in the world. Although the human immune response
is highly effective at controlling the initial infection with
Mycobacterium tuberculosis [1], in some individuals, all viable
organisms may not be eliminated, which leads to a latent
tuberculosis infection (LTBI). People with LTBI are asymp-
tomatic, but they harbor Mycobacterium organisms that can
be reactivated and cause disease under certain circumstances
associated with known risk factors.
It is generally accepted that patients with systemic inflam-
matory diseases are susceptible to TB infection due to the
suppression of their immune systems that can be caused by
steroid or disease modifying antirheumatic drug (DMARD)
treatment or by the presence of the disease itself. Patients with
rheumatoid arthritis (RA) were found to have an increased
observational cohort study from Japan that reported a 3.2-
fold increased risk of TB in RA patients who were treated
with the standard therapy of DMARDs [2]. Although the
introduction of tumor necrosis factor alpha inhibitors (TNF-
i) for the treatment of RA represents a significant advance
in this area, the therapy is associated with an increase in the
incidence of active TB disease among the population of RA
patients [3].
Until about 10 years ago, the tuberculin skin test (TST)
was the only test available to detect LTBI. However, its accu-
racy among certain patient groups is questionable. According
to the Centers for Disease Control and Prevention guidelines,
an induration of ≥ 5 mm is classified as positive in the
following groups: patients with HIV infection, patients who
had recent close contact with TB infected people, patients
who have undergone organ transplants or who are receiv-
ing immunosuppression therapy (e.g., TNF-i, methotrexate,
2 International Journal of Rheumatology
prednisone, and cyclosporine), and patients whose chest
radiographs show fibrotic changes consistent with previous
TB [4]. Although this guideline assigns patients with RA
who are being treated with immunosuppressive drugs to
the group of patients who are at high risk of developing
active TB, it defines neither the dose nor the duration for
immunosuppressive treatments, and it only mentions high-
dose treatments for patients treated with steroids.
Several factors have been cited as confounders of the
TST skin test. Test interpretation is difficult in patients
who received Bacille Chalmette-Guerin vaccine or who were
exposed to nontuberculous mycobacteria. In patients with
rheumatic disease whose immune responses have been com-
promised, TST may also be misinterpreted. Indeed, among
patients with rheumatic disease, test efficacy suffers from low
positive and negative predictive values [4, 5].
The aim of the study was to assess the correlation between
prednisone and methotrexate (MTX) treatment duration and
dosage with the size of the TST reaction among RA patients.
In that respect, the size of the TST reaction was compared
among RA patients with and without prednisone therapy. In
addition, TST reaction size was compared between healthy
subjects (HS) and RA patients who were treated with
immunosuppressive treatments.
Because the main objective of this study was to compare
the distributions of the TST results, assessments of the results
in terms of “positive” or “negative” were not done.
2. Patients and Methods
This retrospective study was performed in the Rheumatology
Unit in collaboration with the Pulmonology Department
at Barzilai Medical Center, Israel. The TST was performed
according to the Mantoux method by injecting 5 tuberculin
units (TU) of purified protein derivative into the inner
surface of the forearm and then measuring the maximal
size of the induration after 72 hours, as recommended [6].
The study was performed in a single center and all TST
measurements were done by a single, highly trained, observer.
Anergy was excluded by repeating the TST within two weeks
for all subjects whose initial TST result was 0 mm. The
second result was considered definitive. Information for the
socio-demographic and TB screening questionnaires was
obtained from medical charts, and current medical history
and treatment were recorded. Overall exclusion criteria were
active TB, known history of active TB, and recent immigrant
(less than 5 years in Israel). In addition, consecutive cases
of RA patients who were candidates for TNF-i therapy
were retrospectively reviewed. TST measurements and pred-
nisone and methotrexate doses and treatment durations were
recorded. Active tuberculosis (TB) was excluded by chest
X-ray and patient history. A control group was randomly
selected from healthy individuals who had undergone a TST
at the pulmonology clinic of our institution.
We compared the results of the mean size of the TST
reaction between the following groups: RA patients who were
undergoing prednisone treatment at the time of the TST,
RA patients without histories of prednisone treatment, and
healthy individuals. A following subanalysis was conducted
40.0%
35.0%
30.0%
% of subjects
25.0%
20.0%
15.0%
10.0%
5.0%
0.0%
0 5 10 15 20 25 30
TST reaction
RA w/o prednisone
RA w prednisone
HS
Figure 1: TST reactions in RA patients treated with prednisone, in
those not treated with prednisone and in controls. TST = tuberculin
skin test; RA = rheumatoid arthritis; HS = healthy subjects.
to include MTX treatments among RA patients. A one-way
ANOVA was used to compare the differences between the
groups. We introduced the score of unit-year (u-y) of the
treatment with regard to mean dose of medication and the
number years that the medication was being taken. We then
calculated u-y scores for prednisone and methotrexate by
dividing the dosage of the medication by its minimal unit (5
mg/day and 2.5 mg/week, respectively) and then multiplying
the result by the number of treatment years. A correlation
between these scores and the size of the TST reaction was
assessed using Pearson's correlation coefficient (r). Values of
p < 0.05 were considered significant.
3. Results
Our study sample comprised of 43 (mean age 57.7 ± 13.1
years, 86% female) RA patients with prednisone treatment,
22 (mean age 59.9 ± 10.8 years, 73% female) prednisone naı̈ve
patients, and 195 (mean age 51.5 ± 10.9 years, 67% female)
healthy subjects (HS). The mean ages between the RA patient
groups and the HS group differed significantly, and therefore,
a significantly higher incidence of systemic hypertension was
found in the RA groups. There was no difference in other
diseases between the groups. The baseline characteristics of
RA patients and HS are shown in Table 1.
We did not find any significant difference in the mean
TST values between the three groups. In RA patients with
prednisone treatment, mean TST size was 5.3 mm ± 6.6 mm;
in the group of RA patients without prednisone treatment,
mean TST size was 7.8 mm ± 6.2 mm; and in the group of HS
mean TST size was 7.6 mm ± 7.0 mm, p = 0.149 (Table 2 and
Figure 1).
No correlation was found between TST size and pred-
nisone [mean u-y = 5.2 ± 5.6, (r = 0.229, p = 0.140)] and
between TST size and methotrexate u-y in patients with
prednisone therapy [mean u-y = 14.4 ± 28.2 (r = 0.219, p =
International Journal of Rheumatology
Table 1: Baseline characteristics of study participants.
Variable RA Patients (n = 65)
Age (yrs) 58.4 ± 12.3
Female (%) 53 (82)
Comorbidities
Systemic hypertension (%) 38 (59)
Diabetes mellitus (%) 10 (15)
Cardiovascular disease (%) 3 (5)
Chronic lung disease (%) 2 (3)
Chronic renal insufficiency (%) 3 (5)
Liver disease (%) 1 (2)
History of malignancy (%) 2 (3)
Table 2: Mean and median TST sizes in RA patients treated with prednisone and RA patients not treated with prednisone and controls.
TST size (mm) RA with prednisone therapy (n = 43) RA without prednisone therapy (n = 22)
Mean ± SD 5.3 ± 6.6
Median 3.0
Range [0, 28]
0.158)] or without prednisone therapy [mean u-y = 30.7 ± 32.4
(r = −0.293, p = 0.186)] (Figure 2).
4. Discussion
An accurate diagnosis of LTBI in patients before starting
TNF-i treatment and subsequent prophylactic anti-TB treat-
ment is critical to prevent TB reactivation. The currently
accepted screening strategy, based on TST, chest x-rays, and
the data collected from the risk stratification questionnaire,
has significantly reduced the rate of TB reactivation under
TNF-i therapy [7]. Despite this success, the correct approach
to diagnosing LTBI is still being debated. The main issue
surrounds the interpretation of TST results among patients
with inflammatory arthritis [8]. In RA patients being treated
with immunosuppressive drugs, misinterpretation can lead to
false negative test results with the potential to cause serious
harm to patients. To avoid false negative results among
patients, the recommended cut-off of induration size is 5 mm.
The results of our study, which did not find attenuation
in TST results among RA patients in comparison with HS
patients, contrasted those of previous studies that showed
an attenuated response [9, 10] but were in agreement with
the results of several other studies [3, 11, 12]. The observed
discrepancies are probably due to differences between certain
features of the countries where the studies were performed.
For example, although in developing countries, the TST
reaction may be attenuated as a result of poor socioeconomic
conditions and of additional diseases status, in developed
countries, these effects are diminished or absent.
Reducing the cutoff value for a positive TST reaction
to 5 mm among RA patients who are being treated with
immunosuppressive drugs may lead to the detection of more
cases of LTBI. Although this increase would come at the cost
of a corresponding increase in the proportion of false positive
results, the reduced cut-off value is justified if the attenuating
3
Controls (n = 195) P value
51.5 ± 10.9 <0.001
131 (67) 0.028
64 (33) <0.001
22 (11) 0.383
16 (8) 0.420
14 (7) 0.372
9 (5) 0.999
9 (5) 0.459
5 (3) 0.999
Controls (n = 195) P value
7.8 ± 6.2 7.6 ± 7.0
4.5 7.0 0.149
[0, 22] [0, 27]
effect that immunosuppressive drugs have on TST size
reaction is strongly proved. High doses of prednisone (more
than 15 mg/d) are known to have an attenuating effect on TST
size about which all studies are in agreement. However, the
efficacy of the long-term treatment of RA patients with low
doses of prednisone (less than 10 mg) has not been definitively
determined [10, 11, 13].
In our study, the use of low-dose prednisone was not
associated with reductions in the TST induration size in RA
patients in comparison to HS patients, even when treatment
had been ongoing for several years. Likewise, MTX had no
effect on TST results as in a previous study [11]. Therefore,
considering the results of our study together with those of
previous works, lowering the cut-off of induration size for the
TST reaction in RA patients may be warranted in locations
with high prevalences of TB infection. In other places, where
the prevalence of TB infection is low, such a decrease may
lead to only a limited reduction in false negative results. In
addition, it could also result in an increase in false positive
TST results and subsequently in the provision of unnecessary
treatment.
Our study has several limitations. First, the small number
of subjects (n = 260) may reduce the chances of obtaining
statistically significant results. Second, we did not analyze
the correlation between TST results and disease activity, and
we could not provide BCG status for the study participants.
However, as our study participants may had received BCG
vaccination only during early childhood, the mean age of the
participants suggests their previous vaccination should not
influence TST, as BCG vaccination protection declines with
time and generally lasts for up to 10 years [14]. Third, although
TST exam is subjective and intraobserver variation can occur,
golden standard of latent tuberculosis diagnosis was not
available to us as QuantiFERON test or Golden T-Spot test is
not routinely performed in our country. Finally, the mean age
of our group of patients in the study was significantly higher
4 International Journal of Rheumatology

30 30
25 25
TST Reaction

TST Reaction
20 20
15 15
10 10
5 5
0 0
0 5 10 15 20 25 30 0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 160.00
Prednisone u-y MTX u-y
(a) (b)
25

20
TST Reaction

15

10

0
0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00
MTX u-y
(c)

Figure 2: Correlation between TST size and (a) prednisone u-y in RA patients with prednisone therapy, (b) MTX u-y in RA patients with
prednisone therapy, and (c) MTX u-y in RA patients without prednisone therapy. TST = tuberculin skin test; u-y = unit years; RA = rheumatoid
arthritis; MTX = methotrexate.

than that of the healthy controls, a scenario that may lead to
lower diameters of TST in the patient group compared with
the healthy controls.
In conclusion, the evidence presented here suggests that
adherence to the accepted TST-based recommendations for
the diagnosis of LTBI based on the cut-off for TST reaction
size of 5 mm may lead to overestimates of the size of the effect
in the form of excessively high numbers of positive results
that, in turn, cause LTBI to be overdiagnosed. Our data elicit
the suggestion that the algorithms used to test for LTBI are
revised, particularly for nonendemic populations. In fact, for
such populations, the substitution of the traditional TST with
newer diagnostic tools like the QuantiFERON assay may be
warranted. Larger studies are needed to verify our results.
Data Availability
The data used to support the findings of this study are
included within the article.
Conflicts of Interest
Olga Reitblat, Tsahi T. Lerman, Ornit Cohen, and Tatiana
Reitblat declare that they have no conflicts of interest regard-
ing the publication of this paper.
References
[1] M. C. Raviglione, D. E. Snider Jr., and A. Kochi, “Global
epidemiology of tuberculosis: morbidity and mortality of a
worldwide epidemic,” Journal of the American Medical Associ-
ation, vol. 273, no. 3, pp. 220–226, 1995.
[2] T. Yamada, A. Nakajima, E. Inoue et al., “Increased risk of
tuberculosis in patients with rheumatoid arthritis in Japan,”
Annals of the Rheumatic Diseases, vol. 65, no. 12, pp. 1661–1663,
2006.
[3] F. Wolfe, K. Michaud, J. Anderson, and K. Urbansky, “Tuber-
culosis infection in patients with rheumatoid arthritis and the
effect of infliximab therapy,” Arthritis & Rheumatology, vol. 50,
no. 2, pp. 372–379, 2004.
[4] J. Keane and B. Bresnihan, “Tuberculosis reactivation during
immunosuppressive therapy in rheumatic diseases: Diagnostic
and therapeutic strategies,” Current Opinion in Rheumatology,
vol. 20, no. 4, pp. 443–449, 2008.
[5] G. Matulis, P. Jüni, P. M. Villiger, and S. D. Gadola, “Detection of
latent tuberculosis in immunosuppressed patients with autoim-
mune diseases: Performance of a Mycobacterium tuberculosis
antigen-specific interferon 𝛾 assay,” Annals of the Rheumatic
Diseases, vol. 67, no. 1, pp. 84–90, 2008.
[6] “Targeted Tuberculin Testing and Treatment of Latent Tuber-
culosis Infection, MMWR ATS/CDC Statement Committee on
Latent Tuberculosis Infection,” https://www.cdc.gov/MMWR/
PREVIEW/MMWRHTML/rr4906a1.htm.
[7] I. Roitt, J. Brostoff, and D. Male, “Hypersensitivity type IV,” in
Immunology, L. Cook, Ed., p. 255, Mosby, Barcelona, Spain, 4th
edition, 1998.
[8] C. A. Black, “Delayed type hypersensitivity: current theories
with an historic perspective,” Dermatology Online Journal, vol.
5, p. 7, 1999.
[9] D. P. de León, E. Acevedo-Vásquez, A. Sánchez-Torres et al.,
“Attenuated response to purified protein derivative in patients
International Journal of Rheumatology 5

with rheumatoid arthritis: study in a population with a high

prevalence of tuberculosis,” Annals of the Rheumatic Diseases,
vol. 64, no. 9, pp. 1360-1361, 2005.
[10] S. Agarwal, S. K. Das, G. G. Agarwal, and R. Srivastava,
“Steroids decrease prevalence of positive tuberculin skin test
in rheumatoid arthritis: implications on Anti-TNF therapies,”
Interdisciplinary Perspectives on Infectious Diseases, vol. 2014,
Article ID 430134, 5 pages, 2014.
[11] K.-H. Lee, S.-Y. Jung, Y.-J. Ha, S.-K. Lee, and Y.-B. Park,
“Tuberculin reaction is not attenuated in patients with rheuma-
toid arthritis living in a region with intermediate burden of
tuberculosis,” Rheumatology International, vol. 32, no. 5, pp.
1421–1424, 2012.
[12] J. D. Greenberg, S. M. Reddy, and S. G. Schloss, “Comparison of
an in vitro tuberculosis interferon-gamma assay with delayed-
type hypersensitivity testing for detection of latent Mycobac-
terium tuberculosis: a pilot study in rheumatoid arthritis,” The
Journal of Rheumatology, vol. 35, pp. 770–775, 2008.
[13] F. Bartalesi, S. Vicidomini, D. Goletti et al., “QuantiFERON-TB
Gold and the TST are both useful for latent tuberculosis infec-
tion screening in autoimmune diseases,” European Respiratory
Journal, vol. 33, no. 3, pp. 586–593, 2009.
[14] I. Abubakar, L. Pimpin, C. Ariti et al., “Systematic review
and meta-analysis of the current evidence on the duration
of protection by bacillus Calmette-Guérin vaccination against
tuberculosis,” Health Technology Assessment, vol. 17, no. 37, pp.
1–4, 2013.
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